- Research purpose: Contribute to the establishment of therapeutic strategy by evaluating the therapeutic effect of Nafamostat by a randomized trial.

- Research background: 
 1. There is no proven therapeutics for COVID-19 patients yet. Currently, the treatment with Kaletra, Hydroxychloroquine, etc. did not show apparent effect, and there are no other drugs that can apply to patients who get worse even with those drugs or severe.
 2. There are research reports that defective innate immunity and accelerated activation of the complement cascade, caused by the SARS-CoV-2, induce rapidly progressing pneumonitis.

* Nafamostat mesilate, ‘serine protease inhibitor’, is used for prevention of perfused blood coagulation when patients with hemorrhagic lesion or tendency to hemorrhage go through extracorporeal circulation instead of heparin, for treatment of patients with Disseminated intravascular coagulation (DIC), and improvement fo symptoms of acute pancreatitis.

※ Proposed Action mechanism of Nafamostat mesilate
A. Show anti-viral effect by an inhibition serine protease, which is required for the host membrane fusion of viral envelop protein. In vitro experiments showed that the drug is effective in MERS-CoV, Influenza virus, and SARS-CoV-2
B. Show anti-inflammatory effect by inhibition of the complement pathway, and inhibition of cytokine production

Treatment

1. Control group: Conventional treatment
 * Conventional treatment: Treatments with Lopinavir / ritonavir, Hydroxychloroquine, Oxygen therapy, Non-invasive and invasive ventilaton, antibiotic therapy, renal-replacement therapy (e.g. CRRT, HD),  extracorporeal membrane oxygenation (ECMO), etc. can be applied as a standard treatment for patients eligible for this study.

2. Intervention group: Conventional treatment + Nafamostat IV
 * Nafamostat injection
- Dosage: The researcher administers a dose of 0.1 to 0.2 mg / kg / hr (2.4 to 4.8 mg / kg / day), taking into account the severity and underlying disease of the clinical trial patient.
- Method of administration: Nafamostat injection is mixed with 1,000 ml of 5% DW infusion, followed by continuous infusion over 24 hours.
- Duration of administration: The researcher administers for 10-14 days considering the severity and underlying disease of the clinical trial patient.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Conventional treatment
: Treatments with Lopinavir / ritonavir, Hydroxychloroquine, Oxygen therapy, Non-invasive and invasive ventilaton, antibiotic therapy, renal-replacement therapy (e.g. CRRT, HD),  extracorporeal membrane oxygenation (ECMO), etc. can be applied as a standard treatment for patients eligible for this study.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Conventional treatment + Nafamostat IV

 * Nafamostat IV injection
- Dosage: The researcher administers a dose of 0.1 to 0.2 mg / kg / hr (2.4 to 4.8 mg / kg / day), taking into account the severity and underlying disease of the clinical trial patient.
- Method of administration: Nafamostat injection is mixed with 1,000 ml of 5% DW infusion, followed by continuous infusion over 24 hours.
- Duration of administration: The researcher administers for 10-14 days considering the severity and underlying disease of the clinical trial patient.

Gender

Age

Description

1. 18 years old or older
2. Patients who have been confirmed of COVID-19 infection and has evidence for pneumonia
A. Confirmation of COVID-19 infection by RT-PCR of SARS-CoV-2 
B. Definite diagnosis of new infiltration of the lungs by chest CT scan of chest radiographic inspection
3. Patients who are within 72 hours of COVID-19 pneumonia confirmation 
4. Patients with 3 (hospitalization, not requiring supplemental oxygen) or higher in seven-category ordinal scale of clinical status
5. Patients who are eligible for diagnosis/evaluation to chest CT scan and related to it
6. Patients should be able to understand the essence of the clinical trial and to submit a written consent document.  For the patients who can understand the nature of the research but cannot sign the document, a relative can agree to the study.

1. Patients who have a record of HIV or AIDS 
2. Female patients, either who are pregnant within 6 months before the investigation, who breast-fed babies within 3 months before the investigation, or who may get pregnant or breast-feed within 1 month after the investigation is over
3. Patients at high risk of death within 3 days of randomized assignment, by the judge of the investigator
4. Patients with liver cirrhosis whose Child-Puch score is B or C
5. Patients who have liver disease abnormalities with ALT or AST > 5 times ULN 
6. Patients who can be in danger or who shows clinically-important other conditions which may interfere with the evaluation or completion of the test procedure, as the investigator’s opinion
7. Patients who are not appropriate for the test, as the investigator’s opinion
8. Patients who have hypersensitivity to the investigational drug

Proportion of patients with clinical improvement as defined by live discharge from hospital or  a decline of 2 categories on the seven-category ordinal scale of clinical status

Day 14 and Day 28

Time from randomization to a decline of 2 categories on the seven-category ordinal scale of clinical status or live discharge from the hospital, whichever came first.

from day 1 through 28 days

Clinical status assessed by 7-category ordinal scale

days 7, 14, 28

Change in National Early Warning Score (NEWS)

from day 1 through day 28

Time to National Early Warning Score (NEWS) of ≤ 2 and maintained for 24 hours

from day 1 through day 28

Duration of hospitalization

from day 1 through day 28

Duration of new non-invasive ventilation or high flow oxygen use

from day 1 through day 28

Incidence of new non-invasive ventilation or high flow oxygen use

from day 1 through day 28

Duration of new supplement oxygen use

from day 1 through day 28

Incidence of new supplement oxygen use

from day 1 through day 28

Duration of new ventilator or extracorporeal membrane oxygenation (ECMO) use

from day 1 through day 28

Incidence of new ventilator or extracorporeal membrane oxygenation (ECMO) use

from day 1 through day 28

Mortality at day 28

from day 1 through day 28

Time (days) from treatment initiation to death

from day 1 through day 28

Viral load change (log10 viral load) of nasopharyngeal swab and sputum sample for SARS-CoV-2 quantitative RT-PCR

day 0,  3, 7, 10, 14, and 21

Adverse events that occurred during treatment

from day 1 through day 28